tbuckley/cabot-search huggingface dataset:
DDM1-mediated gene body DNA methylation is associated with inducible activation of defense-related genes in Arabidopsis
Authors: Seungchul Lee, Jaemyung Choi, Jihwan Park, Chang Pyo Hong, Daeseok Choi, Soeun Han, Kyuha Choi, Tae-Young Roh, Daehee Hwang, Ildoo Hwang
Journal: Genome biology (2023)

Abstract Background Plants memorize previous pathogen attacks and are “primed” to produce a faster and stronger defense response, which is critical for defense against pathogens. In plants, cytosines in transposons and gene bodies are reported to be frequently methylated. Demethylation of transposons can affect disease resistance by regulating the transcription of nearby genes during defense response, but the role of gene body methylation (GBM) in defense responses remains unclear. Results Here, we find that loss of the chromatin remodeler decrease in DNA methylation 1 ( ddm1 ) synergistically enhances resistance to a biotrophic pathogen under mild chemical priming. DDM1 mediates gene body methylation at a subset of stress-responsive genes with distinct chromatin properties from conventional gene body methylated genes. Decreased gene body methylation in loss of ddm1 mutant is associated with hyperactivation of these gene body methylated genes. Knockout of glyoxysomal protein kinase 1 ( gpk1 ), a hypomethylated gene in ddm1 loss-of-function mutant, impairs priming of defense response to pathogen infection in Arabidopsis . We also find that DDM1-mediated gene body methylation is prone to epigenetic variation among natural Arabidopsis populations, and GPK1 expression is hyperactivated in natural variants with demethylated GPK1 . Conclusions Based on our collective results, we propose that DDM1-mediated GBM provides a possible regulatory axis for plants to modulate the inducibility of the immune response.
Echinomycin as a promising therapeutic agent against KSHV-related malignancies
Authors: Jungang Chen, Zhen Lin, Jiao Song, Karlie Plaisance-Bonstaff, Jennifer James, Shengyu Mu, Steven R. Post, Lu Dai, Zhiqiang Qin
Journal: Journal of Hematology & Oncology (2023)

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in immunocompromised patients while lack of effective therapeutic options. Oncoproteins Myc and hypoxia-inducible factor-1α (HIF1α) have been found closely related to KSHV infection, replication and oncogenesis. However, the strategies of dual targeting these two oncoproteins have never been developed and tested for treatments of KSHV-related malignancies. In the current study, we report that treatment of echinomycin dramatically regresses cell growth both in vitro-cultured KSHV + tumor cells and in vivo KS or PEL xenograft mice models, through simultaneously inhibiting Myc and HIF1α expression. Echinomycin treatment also induces viral lytic gene expression whereas not increasing infectious virions production from KSHV + tumor cells. Our comparative transcriptomic analysis has identified a bunch of new Echinomycin-regulated, Myc- and HIF1α-related genes contributed to KSHV pathogenesis, including KDM4B and Tau, which are required for the survival of KSHV + tumor cells with functional validation. These data together reveal that dual targeting Myc and HIF1α such as using Echinomycin may represent a new and promising option for treatments of these virus-associated malignancies.
Gut-specific telomerase expression counteracts systemic aging in telomerase-deficient zebrafish
Authors: Mounir El Maï, Malia Bird, Asma Allouche, Seniye Targen, Naz Şerifoğlu, Bruno Lopes-Bastos, Jean-Marie Guigonis, Da Kang, Thierry Pourcher, Jia-Xing Yue, Miguel Godinho Ferreira
Journal: Nature Aging (2023)

Telomere shortening is a hallmark of aging and is counteracted by telomerase. As in humans, the zebrafish gut is one of the organs with the fastest rate of telomere decline, triggering early tissue dysfunction during normal zebrafish aging and in prematurely aged telomerase mutants. However, whether telomere-dependent aging of an individual organ, the gut, causes systemic aging is unknown. Here we show that tissue-specific telomerase expression in the gut can prevent telomere shortening and rescues premature aging of tert-/-. Induction of telomerase rescues gut senescence and low cell proliferation, while restoring tissue integrity, inflammation and age-dependent microbiota dysbiosis. Averting gut aging causes systemic beneficial impacts, rescuing aging of distant organs such as reproductive and hematopoietic systems. Conclusively, we show that gut-specific telomerase expression extends the lifespan of tert-/- by 40%, while ameliorating natural aging. Our work demonstrates that gut-specific rescue of telomerase expression leading to telomere elongation is sufficient to systemically counteract aging in zebrafish.
miR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism
Authors: Ying Hu, Tahereh Setayesh, Farzam Vaziri, Xuesong Wu, Samuel T. Hwang, Xin Chen, Yu-Jui Yvonne Wan
Journal: Molecular Therapy (2023)

MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is also poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 effectively treated HCC. Compared with FDA-approved lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and T cells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing T cells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC effect of miR-22. Additionally, miR-22 expanded cytotoxic T cells and reduced regulatory T cells (Treg). Moreover, depleting cytotoxic T cells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high HCC had upregulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment. MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is also poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 effectively treated HCC. Compared with FDA-approved lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and T cells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing T cells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC effect of miR-22. Additionally, miR-22 expanded cytotoxic T cells and reduced regulatory T cells (Treg). Moreover, depleting cytotoxic T cells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high HCC had upregulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment.
Methods for deriving risk difference (absolute risk reduction) from a meta-analysis
Authors: M Hassan Murad, Zhen Wang, Ye Zhu, Samer Saadi, Haitao Chu, Lifeng Lin
Journal: BMJ (2023)

Trading off benefits and harms requires knowledge of the absolute risk reduction or risk difference, making risk difference a critical measure for decision making. The confidence interval of risk difference is the basis for imprecision judgments made by guideline developers. Estimating risk difference is not straightforward, however, and the available methods have various limitations. Four methods are discussed in this article. The major limitation of the first method, pooling of risk differences generated from multiple studies in a meta-analysis, is the inconsistency of risk difference across baseline risks. The major limitation of the second method, transforming a pooled relative effect (such as a risk ratio or odds ratio) into a risk difference, is that its confidence interval does not incorporate uncertainty in the baseline risk. This confidence interval widens in a linear fashion as the baseline risk increases, making risk difference estimates in higher risk populations imprecise, and can lead to misleadingly precise risk differences when the baseline risk is low. Two alternative methods can reduce some of these limitations. A simple microsimulation approach can model uncertainties in both the relative effect and the baseline risk. The bivariate random effects model jointly analyzes the risks in treatment and control groups and computes conditional effects based on baseline risks. We apply these four methods to a case study and provide recommendations on when to use each approach. This article also provides practical advice and open source R coding to facilitate risk difference estimation by meta-analysts and guideline developers.
Meta-research studies in surgery: a field that should be encouraged to assess and improve the quality of surgical evidence
Authors: Ivan D. Lozada-Martinez, Cristina I. Ealo-Cardona, Ariel C. Marrugo-Ortiz, Yelson A. Picón-Jaimes, Luis F. Cabrera-Vargas, Alexis R. Narvaez-Rojas
Journal: International Journal of Surgery (2023)

Lozada-Martinez, Ivan David; Ealo-Cardona, Cristina Isabela; Marrugo-Ortiz, Ariel Camilo; Picón-Jaimes, Yelson Alejandro; Cabrera-Vargas, Luis Felipe; Narvaez-Rojas, Alexis Rafael MD Author Information
Fetal Factors Disrupt Placental and Maternal Iron Homeostasis in Murine β-Thalassemia
Authors: Yang Yu, Regina R Woloshun, Jennifer K Lee, Pearl Onuwa Ebea, Sean Zhu, Elizabeta Nemeth, Laura Garrick, Michael Garrick, James F. Collins
Journal: Blood (2023)

Pregnancy rates in β-thalassemia are increasing, but the risk of complications is higher; thus, better understanding of maternal and fetal iron homeostasis in this disorder is needed. HbbTh3/+ (Th3/+) mice model human β-thalassemia. Both the murine and human diseases are characterized by low hepcidin, high iron absorption and tissue iron overload, with concurrent anemia. We hypothesized that disordered iron metabolism in pregnant Th3/+ mice would negatively impact their unborn offspring. The experimental design included these groups: WT dams carrying WT fetuses (WT1); WT dams carrying WT and Th3/+ fetuses (WT2); Th3/+ dams carrying WT and Th3/+ fetuses (Th3/+); and age-matched, non-pregnant adult females. Serum hepcidin was low, and mobilization of splenic and hepatic storage iron was enhanced in all three groups of experimental dams. Intestinal 59Fe absorption was lower in Th3/+ dams (as compared to WT1/2 dams), but splenic 59Fe uptake was higher. Th3/+ dams had hyperferremia, which led to fetal and placenta iron loading, fetal growth restriction and placentomegaly. Notably, Th3/+ dams loaded Th3/+ and WT fetuses, with the latter situation more closely mirroring human circumstances when thalassemic mothers have relatively unaffected (thalassemia trait) offspring. Iron-related oxidative stress, and hypoxia, likely explains impaired fetal growth; enhanced placental erythropoiesis is a probable cause of placental enlargement. Moreover, high fetal liver iron transactivated Hamp; fetal hepcidin downregulated placental FPN expression, limiting placental iron flux and thus mitigating fetal iron loading. Whether gestational iron loading occurs in human thalassemic pregnancy, when blood transfusion can further elevate serum iron, is worth consideration.
The role of flavonoids in the regulation of epithelial‐mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis
Authors: Carina Proença, Marisa Freitas, Daniela Ribeiro, Ana T. Rufino, Eduarda Fernandes, José Miguel P. Ferreira de Oliveira
Journal: Medicinal Research Reviews (2023)

One of the hallmarks of cancer is metastasis, a process that entails the spread of cancer cells to distant regions in the body, culminating in tumor formation in secondary organs. Importantly, the proinflammatory environment surrounding cancer cells further contributes to cancer cell transformation and extracellular matrix destruction. During metastasis, front-rear polarity and emergence of migratory and invasive features are manifestations of epithelial-mesenchymal transition (EMT). A variety of transcription factors (TFs) are implicated in the execution of EMT, the most prominent belonging to the Snail Family Transcriptional Repressor (SNAI) and Zinc Finger E-Box Binding Homeobox (ZEB) families of TFs. These TFs are regulated by interaction with specific microRNAs (miRNAs), as miR34 and miR200. Among the several secondary metabolites produced in plants, flavonoids constitute a major group of bioactive molecules, with several described effects including antioxidant, antiinflammatory, antidiabetic, antiobesogenic, and anticancer effects. This review scrutinizes the modulatory role of flavonoids on the activity of SNAI/ZEB TFs and on their regulatory miRNAs, miR-34, and miR-200. The modulatory role of flavonoids can attenuate mesenchymal features and stimulate epithelial features, thereby inhibiting and reversing EMT. Moreover, this modulation is concomitant with the attenuation of signaling pathways involved in diverse processes as cell proliferation, cell growth, cell cycle progression, apoptosis inhibition, morphogenesis, cell fate, cell migration, cell polarity, and wound healing. The antimetastatic potential of these versatile compounds is emerging and represents an opportunity for the synthesis of more specific and potent agents.
Survival improvement of patients with FLT3 mutated acute myeloid leukemia: results from a prospective 9 years cohort
Authors: Guadalupe Oñate, Marta Pratcorona, Ana Garrido, Alicia Artigas-Baleri, Alex Bataller, Mar Tormo, Montserrat Arnan, Susana Vives, Rosa Coll, Olga Salamero, Ferran Vall-Llovera, Antònia Sampol, Antoni Garcia, Marta Cervera, Sara Garcia Avila, Joan Bargay, Xavier Ortín, Josep F. Nomdedéu, Jordi Esteve, Jorge Sierra
Journal: Blood Cancer Journal (2023)

Abstract Midostaurin added to intensive chemotherapy is the standard of care for acute myeloid leukemia (AML) with FLT3 mutations ( FLT3 mut). We analyzed the impact of midostaurin in 227 FLT3 mut-AML patients included in the AML-12 prospective trial for fit patients ≤70 years (#NCT04687098). Patients were divided into an early (2012–2015) and late (2016–2020) cohorts. They were uniformly treated except for the addition of midostaurin in 71% of late group patients. No differences were observed in response rates or the number of allotransplants between groups. Outcome was improved in the late period: 2-year relapse incidence decreased from 42% vs 29% in early vs late group ( p = 0.024) and 2-year overall survival (OS) improved from 47% vs 61% ( p = 0.042), respectively. The effect of midostaurin was evident in NPM1 mut patients ( n = 151), with 2-yr OS of 72% (exposed) vs 50% (naive) patients ( p = 0.011) and mitigated FLT3 -ITD allelic ratio prognostic value: 2-yr OS with midostaurin was 85% and 58% in low and high ratio patients ( p = 0.049) vs 67% and 39% in naive patients ( p = 0.005). In the wild-type NPM1 subset ( n = 75), we did not observe significant differences between both study periods. In conclusion, this study highlights the improved outcome of FLT3 mut AML fit patients with the incorporation of midostaurin.
Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy
Authors: Mark Jesus M. Magbanua, Lamorna Brown Swigart, Ziad Ahmed, Rosalyn W. Sayaman, Derrick Renner, Ekaterina Kalashnikova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Wen Li, Amy L. Delson, Smita Asare, Minetta C. Liu, Kathy Albain, A. Jo Chien, Andres Forero-Torres, Claudine Isaacs, Rita Nanda, Debu Tripathy, Angel Rodriguez, Himanshu Sethi, Alexey Aleshin, Matthew Rabinowitz, Jane Perlmutter, W. Fraser Symmans, Douglas Yee, Nola M. Hylton, Laura J. Esserman, Angela M. DeMichele, Hope S. Rugo, Laura J. van ’t Veer
Journal: Cancer Cell (2023)

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival in both subtypes. Conversely, ctDNA negativity after NAC correlates with improved outcomes, even in patients with extensive residual cancer. Pretreatment tumor mRNA profiling reveals associations between ctDNA shedding and cell cycle and immune-associated signaling. On the basis of these findings, the I-SPY2 trial will prospectively test ctDNA for utility in redirecting therapy to improve response and prognosis.
Twenty five years in the making: new evidence impacted by covid
Authors: Alastair D Hay
Journal: BMJ (2023)

Twenty five years in the making: new evidence impacted by covid Alastair D Hay GP andprofessor of primary careThe most common problem managed in primary care globally are acute respiratory tract infections (aRTIs) in children.Around 50% still receive antibiotics in the UK, with 50% of these considered unnecessary.Research to improve antibiotic use in this group is urgently needed.
When I use a word . . . Medical definitions: Pharmacovigilance signals
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

In seeking evidence of adverse drug effects and adverse drug reactions, those working in pharmacovigilance recognise the phenomenon of a signal that raises the suspicion of a causal relation between a drug and an adverse effect or reaction. Manfred Hauben and I, based on etymology, usage, previous definitions, and the processes involved, have defined a signal of suspected causality as follows: <b>signal of suspected causality</b><i>n</i>. information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, which would command regulatory, societal, or clinical attention, and is judged to be of sufficient likelihood to justify verificatory and, when necessary, remedial actions This definition, with small variations, was republished by the Council for International Organizations of Medical Sciences (CIOMS) in 2010 and was adopted by one of its working groups in 2020. We take this as a signal of approval of the definition.
Parallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells
Authors: Rocío Chamorro González, Thomas Conrad, Maja C. Stöber, Robin Xu, Mădălina Giurgiu, Elias Rodriguez-Fos, Katharina Kasack, Lotte Brückner, Eric van Leen, Konstantin Helmsauer, Heathcliff Dorado Garcia, Maria E. Stefanova, King L. Hung, Yi Bei, Karin Schmelz, Marco Lodrini, Stefan Mundlos, Howard Y. Chang, Hedwig E. Deubzer, Sascha Sauer, Angelika Eggert, Johannes H. Schulte, Roland F. Schwarz, Kerstin Haase, Richard P. Koche, Anton G. Henssen
Journal: Nature Genetics (2023)

Abstract Extrachromosomal DNAs (ecDNAs) are common in cancer, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity are still unresolved. Here we describe single-cell extrachromosomal circular DNA and transcriptome sequencing (scEC&amp;T-seq), a method for parallel sequencing of circular DNAs and full-length mRNA from single cells. By applying scEC&amp;T-seq to cancer cells, we describe intercellular differences in ecDNA content while investigating their structural heterogeneity and transcriptional impact. Oncogene-containing ecDNAs were clonally present in cancer cells and drove intercellular oncogene expression differences. In contrast, other small circular DNAs were exclusive to individual cells, indicating differences in their selection and propagation. Intercellular differences in ecDNA structure pointed to circular recombination as a mechanism of ecDNA evolution. These results demonstrate scEC&amp;T-seq as an approach to systematically characterize both small and large circular DNA in cancer cells, which will facilitate the analysis of these DNA elements in cancer and beyond.
A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma
Authors: Jehan Alladina, Neal P. Smith, Tristan Kooistra, Kamil Slowikowski, Isabela J. Kernin, Jacques Deguine, Henry L. Keen, Kasidet Manakongtreecheep, Jessica Tantivit, Rod A. Rahimi, Susan L. Sheng, Nhan D. Nguyen, Alexis M. Haring, Francesca L. Giacona, Lida P. Hariri, Ramnik J. Xavier, Andrew D. Luster, Alexandra-Chloé Villani, Josalyn L. Cho, Benjamin D. Medoff
Journal: Science Immunology (2023)

Asthma is a chronic disease most commonly associated with allergy and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, we compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. In response to allergen, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls.